Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway
Inna Astapova, … , David E. Cohen, Anthony N. Hollenberg
Inna Astapova, … , David E. Cohen, Anthony N. Hollenberg
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):1976-1986. https://doi.org/10.1172/JCI73419.
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Research Article Hepatology

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Abstract

Transcriptional coregulators are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoRΔID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoRΔID in mouse liver improves dietary cholesterol tolerance in an LXRα-independent manner. NCoRΔID-associated cholesterol tolerance was primarily due to diminished intestinal cholesterol absorption as the result of changes in the composition and hydrophobicity of the bile salt pool. Alterations of the bile salt pool were mediated by increased expression of genes encoding the bile acid metabolism enzymes CYP27A1 and CYP3A11 as well as canalicular bile salt pump ABCB11. We have determined that these genes are regulated by thyroid hormone and that TRβ1 is recruited to their regulatory regions. Together, these data indicate that interactions between NCoR1 and TR control a specific pathway involved in regulation of cholesterol metabolism and clearance.

Authors

Inna Astapova, Preeti Ramadoss, Ricardo H. Costa-e-Sousa, Felix Ye, Kaila A. Holtz, Yingxia Li, Michele W. Niepel, David E. Cohen, Anthony N. Hollenberg

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Figure 1

Hepatic cholesterol synthesis and deposition in L-ΔID mice.

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Hepatic cholesterol synthesis and deposition in L-ΔID mice. (A) The ra...
(A) The rate of neutral sterol synthesis was assessed in primary hepatocytes isolated from L-ΔID and control mice by incorporation of 3H2O. Shown are data from 1 representative experiment (n = 4 wells per genotype). Expression of Hmgcr was measured by QPCR in the hepatocytes from the same experiment (n = 3 wells per genotype). (B) Representative H&E-stained sections of livers from animals with indicated genotypes after 3 weeks on 2% cholesterol diet. Original magnification, ×20. (C) Hepatic cholesterol content was measured in control and L-ΔID mice on Lxra+/+ and Lxra–/– background after 3 weeks on 2% cholesterol diet (n = 5–11 animals per group). Statistical analysis was performed using unpaired Student’s t test (A) or 2-way ANOVA with Bonferroni post-tests (C). **P ≤ 0.01; ***P ≤ 0.001.